Cocaine dependent individuals, particularly women, frequently cite psychological stress/negative mood as reasons for relapse to drug use, However, there is little understanding of how stress/negative mood increases the risk of relapse in men and women. Preclinical research indicates that stress increases cocaine self-administration and cocaine reinstatement involves via interaction of brain stress systems, namely corticotrophin releasing factor (CRF)-hypothalamic-pituitary-adrenal (HPA) axis and central noradrenergicsympatho- adrenomedullary pathways with reward circuits. Our previous work with cocaine dependent individuals has shown that imagery exposure to stress and to drug cue situations reliably increases cocaine craving, physiological arousal and activates the above brain stress systems. Pilot data also suggests sex differences in stress-induced and drug cue-induced activation of these systems. In addition, early trauma, stress/drug cue reactivity and recent stressors each are significantly associated with cocaine relapse in women as compared to men. Thus, in a sample of 150 treatment-seeking cocaine dependent men and women (75 men and 75 women), we will systematically examine sex differences in the association between early trauma, recent stressors, stress/drug cue reactivity and cocaine relapse. The following specific aims will be addressed: (1) To examine sex differences in measures of cocaine craving, emotion state, HPA activation, plasma catecholamine response and physiological arousal in response to stress imagery, drug cue imagery and neutral imagery; (2) To examine sex differences in the association between early trauma, recent stressors and stress/drug cue reactivity. (3) To assess sex differences in the effects of recent stressors, early trauma history and reactivity to stress/drug cues on cocaine relapse after inpatient cocaine treatment; (4) To explore whether demographic and individual difference variables such as race, age, psychiatric co-morbidity, frontal executive functioning and cocaine dependence severity are significantly associated with stress/drug cue reactivity and cocaine relapse. Findings from this study will have important implications for the development of sex-specific treatment approaches in preventing cocaine relapse in women.